Methods and devices for in vivo targeted light therapy

ABSTRACT

Catheter-based systems for in-vivo targeted light therapy include a first type of catheter configured for photo-activating photosensitive substances in tissue, and a second type of catheter configured for photo-degrading photosensitive substances in tissue. The catheters may be configured to produce light using a variety of light sources, such as light emitting diodes (LEDs) and fiber optics. The light transmission is directed to tissue in such a way that only portions of tissue in a treatment area are exposed to light, depending upon whether the tissue is diseased or healthy.

This is a divisional application of U.S. application Ser. No. 12/191,200filed Aug. 13, 2008, the contents of which are hereby incorporated byreference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods and devices for using light energy andphoto-sensitive substances during the course of a drug therapy.

2. Description of the State of the Art

Photodynamic therapy (PDT) involves the delivery of chemical compounddrugs called photosensitizers into tissue and then exciting thephotosensitizer in order to enable an energy transfer from thephotosensitizer to a nearby oxygen molecule. This produces an excitedsinglet state oxygen molecule that reacts with nearby bio-molecules.With respect to typical cardiovascular applications of PDT, thisreaction causes localized damage in the target atherosclerotic tissue,thereby providing a beneficial effect to the patient.

Photochemical degradation occurs when a compound is exposed to highamounts of light which correspond to the absorbance band of thecompound. The general mechanism for this degradation involves theabsorption of light energy by electrons in chemical bonds. This energycauses the electrons to move to a higher energy state, which can producea reactive region in the molecule. These reactive regions are morelikely to interact with other compounds, notably oxygen, which can breakor alter the chemical bond in the compound, resulting in an overalldegradation of the chemical.

SUMMARY OF THE INVENTION

The invention is directed to methods and devices for drug delivery usinglight to activate one or more drugs and/or to degrade a drug's potency.In either case, the invention teaches various devices and methods forperforming targeted drug therapy for various types of anatomy. Among thebenefits, devices are provided that can reduce the complexity of aprocedure associated with light-based drug therapy, such as PDT,photo-chemical degradation, and activation of a photo-cross-linkabletherapeutic loaded hydrogel. Features of the invention provide a saferworking environment for light-based drug therapy, improve the ability todeliver light energy sufficient to activate or degrade a drug in tissue,improve the ability to activate or degrade a drug's potency at anintended location, but not elsewhere, reduce a patient's “dark time”,which is intended to mean the period when a patient administered with aphoto-activated substance must not be exposed to light, and/or enablemore precise targeting of tissue for drug therapy.

In accordance with one or more of the foregoing objectives, a deviceconfigured to perform light-based therapy, e.g., PDT, may integrateflexible electronics at a distal portion thereof, including lightemitters and light detectors. In some embodiments, one or more arrays oflight emitting diodes (LEDs) are positioned near a working end of amedical device, e.g. a balloon catheter. The LEDs generate light thatexcites a photosensitizer and initiates PDT of adjacent tissue.Photodiodes may be used in combination with the LEDs to detect reflectedlight from the anatomy. Depending on the magnitude of the detectedlight, the photodiodes may transmit a signal that causes the LEDs toeither be powered on or off. In this way, a closed loop control systemmay be used to perform light therapy, e.g., PDT, in a safe and efficientmanner. The closed-loop system may be entirely located at the distalportion of the device.

In accordance with one or more of the foregoing objectives, embodimentsof the invention include a catheter configured such that a power supplyprovides electrical power to a distal portion of a catheter, which issafer and easier to implement than Class III lasers that are sometimesused for light therapy, e.g., PDT. In addition, electrical power leadsmay be more flexible, and thus more deliverable, than fiber optics thatare sometimes used for light therapy, e.g., PDT. Additionally, a closedloop control design according to embodiments of the invention may reducedamage of healthy tissue by deactivating LEDs adjacent to healthytissue. Additionally, a closed loop control design improves powerconsumption and optimizes light delivery of a diode array to improveefficiency and efficacy of PDT.

According to one aspect of the invention, there are methods and devicesfor activating photosensitizers in order to initiate a light therapy,e.g., PDT, photochemical degradation, activation of aphoto-cross-linkable therapeutic loaded hydrogel. It is particularlyuseful in bodily vessels since the disclosed methods and devices enabletracking through small diameter vessels such as cardiovascular vessels.

The invention includes the recognition that with the emergence of drugeluting stents (DES) for the treatment of cardiovascular disease, thereexists a potential for drug interactions that may not have beenconsidered in a stent's original design or drug elution profile. Forexample, if a DES of one drug was used in close proximity to a DES of adifferent drug, there would exist a potential for a drug interactionwhich may not have been characterized by either producer of the stents.In another example, if two drug eluting stents were placed overlappingin vasculature, the overlapping region would effectively contain twicethe designed dose of drug. This dose may cause a sub-optimal clinicaloutcome. In another example, the diffusion of a drug away from thedrug-eluting source could be reduced to a very local region by exposingthe proximal and distal ends of the drug-elution device to a degradinglight source.

In accordance with one or more of the foregoing objectives, methods anddevices are provided that enable an operator to selectively degradeunwanted drug in blood vessels or other anatomy using light. This isuseful in such cases as when a DES or drug coated balloon with aspecific active agent, e.g., Everolimus, is placed near a DES with adifferent active agent, e.g., Paclitaxel. In such cases, an operator maydegrade the drug proximal to a prior implanted stent to prevent possibledrug interaction. Drug interaction may occur due to drug diffusion intoadjacent tissue, one DES overlaps another implanted DES etc. In otherembodiments selective degrading of drugs can allow an operator todegrade an excess of the same DES drug, e.g., if two DES stentsoverlapped, the operator can reduce the possibility of introducing adoubling of the dosage by degrading the drug present in an overlappingregion of two DES using light therapy. Other embodiments would allow anoperator to focus drug exposure to a very specific region of interest bypreventing a diffusion of the drug away from the site of delivery.

In accordance with one or more of the foregoing objectives, acatheter-based system contains two components. One component is a drugdelivery device. This device can be in the form of a DES, drug coatedballoon, bio-absorbable drug eluting stent, a double balloon with drugperfusion, or any other drug delivering device used in vasculature. Thesecond component would be a light source capable of delivering aspecific wavelength or wavelengths of light radiation in a targetedmanner. The light source may include light emitting diodes, a fiberoptic cable with diffuser, a fiber optic cable with a microlens,thin-film diodes, organic light emitting diodes, or any other lightsource capable of specific, targeted light dosing. The wavelength(s) oflight chosen for treatment may depend on the absorbance band of the drugintended to be degraded. Multiple light wavelengths could be utilized tooptimize drug degradation and also the penetration depth of exposure.For instance, longer wavelengths of light, although having less energy,are able to penetrate further into body tissue than shorter wavelengths.Light wavelength and intensity may be optimized in this sense, e.g.,longer wavelengths for deeper penetration, shorter wavelengths for highenergy, to improve the effectiveness of a treatment. For example,optimized wavelength and intensity can promote efficacy towardsreduction of restenosis and improve re-endothelialization and long termDES safety. Both stent and balloon coatings can be chosen for optimaldegradation.

A drug coated region could be any drug eluting source, e.g., a stent orballoon coated surface. Tissue would be exposed to light energy by wayof windows formed as part of a balloon membrane. Select wavelengths maybe allowed to pass through the membrane's windows, while otherwavelengths are blocked. In other embodiments, the windows may betransparent, thereby allowing all light to pass through the membrane (inthis case the light source may only emit certain bands of light). Thegrating of the window and/or wavelength of light may be chosen based onthe absorbance band for the substance being used. The window(s) orlight-blocking location(s) on the membrane would determine the effectivearea the drug would be allowed to expose at full strength. In onerespect, a balloon membrane may be constructed with combinations oflight filters, e.g., UV, near infra red (NIR), white light, all light,etc. Diffused light may be used in these embodiments. A distal orproximal light source may be used. It will be appreciated that a broadspectrum of light wavelengths may be delivered toward the tissue inaccordance with this invention; however, this may not be ideal since itis generally desirable to limit the energy that is delivered into thetissue to prevent excessive heating, for example.

According to one embodiment, a balloon catheter having a window would beused as a DES delivery device. The window can allow for a certainportion of the drug on the stent length to be deactivated in order toprevent the vessel from being exposed to a double dose of drug.

According to another embodiment, windows may be replaced with lightsources attached distally, proximally, or both relative to the balloon.One advantage of this design would be a greater exposure as compared toa light source confined to a pressurized balloon chamber. In theseembodiments, a degrading light source can expose larger portions ofadjacent to tissue to degrade drug that may have diffused quickly afterbeing deposited at a target tissue.

“Target tissue” refers to the tissue that is diseased or abnormal thatwill be, or is intended to be, treated by a medical device according tothe disclosure. In some embodiments, the medical device is configured toexpose the target tissue to light energy, e.g., for photo-activation ofa substance present in the target tissue. In other embodiments, amedical device is configured for light exposing healthy tissue that maybe present adjacent to a treatment area. A “treatment area” refers tothe general location of the target tissue. A treatment area includes, inaddition to the target tissue, healthy or normal tissue that is adjacentthe target tissue.

In other embodiments, a targeted drug therapy as taught by the inventionmay be used in vasculature, as well as in cancer treatment for a varietyof anatomy. For example, tumors may be treated with a potent compoundand the regions proximal to the tumor could be exposed to light of aspecific wavelength to decrease the spread of the potent compound toother tissues. For tissues that diffuse drugs rapidly, light could beused to slow or control the diffusion of the drug, limiting its effectsto the targeted region.

Most light-activation therapies require a patient to spend many hourswithout exposure to light due to the reactivity of the photosensitizerused in these therapies. The disclosed methods and devices provide waysin which to expose a patient to a wavelength of light that woulddegrade, as opposed to activate, a photosensitizer. This featureprovides an approach for reducing the amount of photosensitizer inunwanted areas, e.g., skin, and may even reduce the overall half-life ofa drug in the body. This can also reduce the “dark time” for thepatient, i.e., the amount of time the patient cannot be exposed to lightdue to the presence of light-activated substances in his/her body.

According to another embodiment, a device may provide both a drugactivating wavelength and a degrading wavelength. The drug activatingwavelength could be focused on a region requiring therapy, while thedegrading wavelength could be used to prevent the spread of a drug toadjacent tissue. This technique may be especially useful during thetreatment of a cancerous tumor, as discussed above. For example, aballoon membrane may be configured with multiple light filters(drug-activating and drug-degrading light filters). In another example,a drug-activating light source may be emitted from the balloon anddrug-degradation light source emitted from a catheter shaft at distaland/or proximal locations relative to the balloon.

Methods and devices disclosed herein may also be utilized in combinationwith a delivery of a photo-cross-linkable therapeutic loaded hydrogel(e.g. gel paving or needle injection) via double balloon infusion orcoated balloon that is later exposed and polymer gelled.

According to another aspect of the invention, the methods and devicesdisclosed herein may be utilized for a combined delivery of multipletherapeutics such as an anti-inflammatory drug (e.g. dexamethasone) or-olimus drug in combination with a photosensitizer. For example, “endeffects” are known to be especially troublesome in terms of restenosis.It may not be desirable to activate a photosensitizer along an entirelength of a stent, since the damage to the vessel may be unwarrantedgiven the therapeutic effect that the stent will provide. However,light-activation at the end regions of the stent may contribute to anoverall improvement in therapy, and specifically, to a decrease inrestenosis at the stent ends. A stent may therefore be photo-activatedby directing light of a select wavelength towards a portion of thetissue in a treatment area, so as to activate a previously deliveredphotosensitizer at the ends.

According to one embodiment, a catheter having distal and proximalportions includes a balloon, or a balloon and stent, located at thedistal portion, and a light emitting member located adjacent theballoon. The balloon and light emitting member are configured such thata first portion of the tissue is prevented from receiving light while asecond portion of the tissue is exposed to light. The light emittingmember may include a plurality of light-emitters and light detectors,and a control system disposed at the distal portion and configured foractivating the light-emitters based on signals received from thelight-detectors. The light-emitters are light-emitting-diodes (LEDs) andthe light-detectors are photodiodes. In other embodiments the balloonhas a membrane formed from balloon material, such that the balloonmaterial forms a first balloon portion configured to block all lighttransmission or allow transmission of light at a first wavelength, andthe balloon material forms a second balloon portion configured to allowtransmission of light at a second wavelength. The first and secondwavelengths may correspond to near infra red, IR, visible and/or UVlight wavelengths.

According to another embodiment a catheter having distal and proximalportions and configured for treating tissue in a treatment area, meansfor producing light at the distal portion, and means for exposing only aportion of the tissue in the treatment area to the light. The means forexposing only a portion of the tissue in the treatment area to the lightmay include logic located at the distal portion of the catheter andconfigured for selective illumination of tissue. The means for producinglight may include light emitters and light detectors, and the means forexposing only a portion of the tissue in the treatment area to the lightmay include turning a portion of the light detectors on or off dependingon one or more signals received from the light detectors. The means forexposing only a portion of the tissue in the treatment area to the lightmay include a balloon having a light blocking portion and a lightadmitting portion. The means for exposing only a portion of the tissuein the treatment area to the light may also include a balloon and lightguides disposed distally and/or proximally of the balloon.

According to another embodiment, a method of in vivo light therapy usinga catheter includes the steps of locating a balloon of the catheter at atreatment area, wherein at least a portion of the balloon is locatedopposite a target tissue, and exposing only a portion of tissue in thetreatment area to light energy using a light member, wherein theremaining tissue in the treatment area is not exposed to light energyeither because the tissue is not opposite activated portions of thelight member or the remaining tissue is shielded from the light energy.This method may further include the step of producing a signal inresponse to light emitted from the light member, and initiating lighttherapy including emitting light from the light member if the signal isequal to a first value and not emitting light if the signal is equal toa second value. The locating step may include placing a surface of theballoon having a drug disposed thereon in contact with a target tissue,and then exposing only the tissue adjacent the target tissue to lightenergy. The method of in-vivo light therapy may also includeilluminating tissue adjacent the target tissue including transmittinglight from a first balloon portion, or transmitting light from a lightemitting member located distally and/or proximally of the balloon.

The method of in vivo light therapy may include deploying a first drugeluting stent (DES) mounted to the balloon, and then exposing to lightenergy only the tissue that is opposite an end of the implanted firstDES. The DES may be deployed adjacent a second, previously implantedDES. The second DES may place a first drug in tissue and the first DESmay place a second drug in the tissue. In this embodiment, the exposingto light energy step degrades one of the first and second drugs.

According to another embodiment, a catheter's balloon has a membranewall including a first wall portion formed from a material thattransmits light of a first wavelength and a second wall portion thattransmits light of a second wavelength or substantially prevents alllight transmission; and the catheter includes a light emitting membranedisposed within the membrane. The catheter may further include a stentmounted on the balloon.

According to another embodiment, a method for treating tissue using adrug eluting stent (DES) includes the steps of deploying the DES in avasculature containing a target tissue and exposing tissue locatedopposite an end of the deployed stent to light energy. The exposingtissue step may include exposing tissue to drug-degrading light energy.The deploying step may include deploying the DES adjacent a second DES.

One or more of the foregoing features of invention may also be practicedin the context of other in vivo procedures that rely on a targeted,local delivery of a drug in a blood vessel or other anatomy.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is side, partial cross-sectional view of one embodiment of aballoon catheter according to the disclosure.

FIG. 2 is a front cross-sectional view of the balloon catheter taken atSection II-II in FIG. 1.

FIGS. 3A-3B are schematic illustrations of features associated with anarray of light emitters (e.g., LEDs) and array of light detectors (e.g.,photodiodes) located at a distal portion of the balloon catheter ofFIG. 1. FIG. 3A depicts the light emitted from the LEDs and reflectedtowards the photodiodes when the balloon catheter's distal portion ispositioned at a treatment area that has both abnormal and healthytissue. FIG. 3B depicts a distribution of lighting corresponding to thelocations of abnormal tissue and healthy tissue.

FIG. 4 is a flow diagram relating to a procedure for performing lighttherapy on a target tissue.

FIG. 5 is a partial view of a balloon catheter located at a treatmentarea according to another aspect of the disclosure.

FIG. 6 is a side view of a distal portion of a second embodiment of aballoon catheter located at a treatment area according to thedisclosure.

FIG. 7 is a side view of is a side view of a distal portion of a thirdembodiment of a stent delivery catheter and prior implanted stentlocated at a treatment area according to the disclosure.

FIG. 8 is a bar-chart showing the effectiveness of drug degradationusing light for Everolimus combined with a photosensitizer in a solutionof methanol.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the disclosure a catheter includes on-boardelectronics including an array of light-emitters and light-detectors.The electronics may be located at a distal portion such that asubstantial amount of control of the light-emitters and light-detectorsresides at the distal portion of the catheter. In some embodiments, theelectronics are configured to provide closed-loop control of thelight-emitters. In this way, the catheter may determine the desiredlight distribution on tissue that contains photo-degraded and/orphoto-activated substances. In a preferred embodiment, the catheter'son-board electronics decide whether to turn on, or turn-off alight-emitting diode (LED) based on the differences between themagnitude of reflected light between healthy and abnormal tissue.

FIG. 1 depicts a side, partial view of a balloon catheter 1 shown inpartial cross-section. FIG. 2 depicts a frontal cross-section of thecatheter 1 taken at section II-II in FIG. 1. The catheter 1 has a distalportion 12 and a proximal portion 14. A balloon assembly 6 resides atthe distal portion 12. A shaft 2, which may be a composite shaftconstructed to achieve a desired flexibility, rigidity, deliverability,etc. extends from the distal portion 12 to the proximal portion 14 ofthe catheter 1.

Various lumens are formed by the shaft 2. These lumens, which are formedover a portion or approximately the length of the catheter shallgenerally be referred to as aspects of shaft 2, e.g., shaft body portion2 a, 2 b, etc (see below). However, the disclosure is intended toencompass any catheter known in the art that is capable of providing therequired lumens and performing the specified functions of those lumensin accordance with the disclosure. As such, the disclosure is notlimited to a particular type of catheter. Rather, it applies to, e.g., aunitary or composite-type catheter, Over-The-Wire (OTW) orRapid-Exchange (RX) type catheter, etc. Examples of balloon cathetersare described in U.S. Pat. No. 7,131,963 and US Pub. No. 2008/0025943. Aguide wire 11 is used to guide the catheter 1 to a treatment area thatincludes the target tissue. In an alternative embodiment, catheter 1 maybe a fixed-wire type catheter that does not require guide wire 11 forguidance through a patient anatomy.

Referring to the cross-sectional views in FIGS. 1 and 2, at the distalportion 12 a tubular body portion 2 b of shaft 2 extends from a proximalend 6 b of the balloon portion 6 to a distal end 6 a thereof. Body 2 bdefines the portion of the balloon's inflation lumen between ends 6 aand 6 b. The outer surface of body 2 b may have a multi-sided face,e.g., 8-sided, for purposes of mounting electronics as will be discussedshortly. Body 2 a defines the portion of the catheter's guide wire lumenbetween ends 6 a and 6 b. Bodies 2 a, 2 b may be portions of a compositeor integral shaft.

The balloon 7 may be made of material that can transmit broadband ornarrow-band light. Hence, the balloon membrane may be constructed from atransparent-type balloon material so that very little light energy isreflected or absorbed by the membrane; or the balloon material may beconstructed from a material that absorbs or reflects light of certainwavelengths, while allowing light of other wavelengths to pass through.Balloon material possessing a combination of light filtering propertiesmay also be desirable. Preferably, a folded or pleated balloon type isused. This is primarily to ensure that light transmissive and opaquesegments are accurately placed during inflation, since the balloon ofthis invention need not be a high pressure balloon. Thus, compliantballoons may also be used, which may not require folding or pleating butinstead will be configured significantly circumferentially at alloperational diameters. The ends of the balloon 7 are secured at ends 6a, 6 b to shaft 2 by, e.g., an adhesive; however, in an alternativeembodiment, the balloon ends 6 a, 6 b may be secured to the shaft usingother chemical or thermal welding processes The balloon 7 is inflated bya fluid delivered to the balloon via the inflation lumen (formed in-partby body 2 b). Body 2 b includes an aperture 6 c which puts the inflationlumen in fluid communication with balloon chamber 7 a. Thus, as a fluid(gas or liquid) is passed through the inflation lumen the fluid exitsthrough aperture 6 c to pressurize the balloon 7. The balloon 7 is shownin a fully expanded state in FIG. 1.

Referring to FIG. 1, the catheter 1 includes arrays of light emitters(e.g., light emitter 28) and light detectors (e.g., light detector 26)disposed on substrates 30. These light emitters and detectors are usedto selectively photo-activate agents in tissue. One aspect of thecatheter 1 according to the disclosure is the on-board ability at thedistal portion 12 to selectively turn on or off light emitters as thecatheter 1 is positioned near the treatment area. In this way, thecatheter 1 can produce an energy flux only at, e.g., the target tissue,based on a distribution of light received over the body 2 b of thecatheter 1. This light is detected by the light detectors.

Referring to FIGS. 1 and 2, a plurality of semiconductor substrates 30are arranged on the exterior surface of the body 2 b or integral withthe outer surface of body 2 b. Each of the substrates 30, e.g.,substrate 31 a, preferably contain several Light-Emitting-Diodes (LEDs)for emitting light and photodiodes for detecting light. In otherembodiments, the light source may include thin-film diodes, organiclight emitting diodes, or any other light source capable of specific,targeted light dosing and disposed on a circuit board meeting thefootprint requirements of a catheter intended for in vivo light therapy.The wavelength(s) of light chosen for treatment may depend on theabsorbance band of the drug intended to be activated or degraded.

The LEDs and photodiodes are arranged in longitudinally extending stripsso as to provide an LED array light emitting and photodiodelight-detecting capability over the catheter length extending betweenends 6A and 6B. These LEDs and photodiodes may be operated by acontroller unit 34 disposed at the distal portion 12. The catheter 1 mayinclude a power cord 38 that provides power to a controller 34 andcircuitry associated with LED and photodiode chips. The controller 34may be formed by depositing material onto a plastic substrate in orderto form a flex circuit. Since the substrate is flexible, it may beformed radially about the catheter body. One example of material that issuitable for a flex circuit substrate is Polyimide. The power cord 38may pass through the inflation lumen. At the distal portion 14 the powercord 38 exits through a port 14 a. A connector 42 may be provided toconnect the power cord to a power source. As depicted, the catheter mayinclude eight longitudinally extending substrates, i.e., 31 a-31 h, thatare disposed on eight sides of body 2 b (FIG. 2). Each substrate has anarray of photodiode-LED pairs. For instance, in the cross-sectional viewof FIG. 2 LED-photodiode pairs 22 a-22 h correspond to one of theLED-photodiodes disposed on each of the respective substrates 31 a-31 h.The substrates 31 may be integrated into the body 2 b or adhered,attached, etc. to the body 2 b. The substrates 31 and/or body 2 b mayinclude heat sinks that transfer heat generated by the LEDs to an innerlumen, e.g., inflation lumen, by way of metallic heat paths extendingradially through body 2 b. Transfer or heat isolation may also beachieved by a circulating fluid, e.g., inflation fluid, or flushingfluid passed through, e.g. the lumen formed by body 2 b.

A substrate such as substrate 31 a may correspond to a portion of acircuit board including other substrates, e.g., adjacent substrates 31 band 31 h, or an individual circuit board having its own input/output forelectrically communicating with the controller 34. In a preferredembodiment, a circuit board may contain several tightly packedLED/photodiodes manufactured by Stocker Yale, Inc., 32 Hampshire Road,Salem, N.H. 03079 (http://www.stockeryale.com/i/leds/). Each array 31a-31 g may correspond to such a circuit board.

As was just recently mentioned, each LED may be paired with a photodiodeas in, e.g., LED-photodiode pairs 22 a, 22 b, and 22 c (LEDs aredistinguished from photodiodes in the drawings by hash-marks overphotodiodes). The pair may be designed to operate as follows. The LEDportion emits light towards adjacent tissue. Light reflected, emitted orscattered from the tissue is detected by the adjacent photodiode. Theamplitude of this light energy is then communicated to the controller 34from the photodiode by an electrical signal that is proportional to themagnitude of the detected light energy. The controller 34 may then beprogrammed to turn the LED “on” or “off” based on the magnitude ofelectrical signal received from the photodiode. By placing the LED andphotodiode in pairs, the controller 34 may need only simple logic sinceit may in some cases be assumed that light detected at a photodiodeoriginated substantially from the adjacent or closest LED. For example,the controller 34 logic may assume that whenever a signal above acertain threshold is produced by the photodiode portion ofLED-photodiode pair 22 a, the signal was caused substantially by the LEDportion of this pair, i.e., the closest LED. Other logic may be used todetermine which LED lights were the cause of a signal produced by aphotodiode.

A catheter according to the disclosure need not assume that the majorityof light received by a photodiode was the result of light emitted fromthe adjacent LED. For instance, the catheter 1 may execute an on-boarddiagnostic or calibration routine before reaching a treatment area todetermine how LED light is reflected from tissue when the catheter isplaced in similar anatomy, e.g., similar vasculature, as the treatmentarea (absent the abnormal tissue). The controller 34 would initiate anon-off cycle over all LEDs, recording the magnitude of the signalproduced at a photodiode during the brief time that each individual LEDis the only LED emitting light. Then, the LED corresponding to thehighest magnitude electric signal produced by the photodiode isdesignated as the LED that will be turned on/off based on the signalreceived from this photodiode. This procedure may then be repeated forall photodiodes. At the end of this calibration, the controller hasassigned or cross-referenced one or more LEDs with a signal produced ateach of the photodiodes. Accordingly, when the catheter arrives at thetreatment area, the controller determines which LED(s) to turn on or offby cross-referencing the photodiode signals with the correspondingLED(s).

The logic according to the disclosure may therefore be used to determinewhich LEDs to de-energized or turn off when the electrical signalproduced by a photodiode is above a certain threshold. “On/off” signalcommands to LEDs may be produced by the controller 34 by opening/closingswitches, and the photodiode signals communicated to the controller 34in order to decide which LEDs should be turned on or off. In someembodiments the controller 34 may have programmable logic or hard-wired(i.e., non-programmable) logic.

In other embodiments a controller may not be needed. According to theseembodiments, a substrate may include circuits that have their own logicbuilt-in for deciding whether an LED remains on or off. For example, foran embodiment that has LED-photodiode pairs, a signal produced by thephotodiode may turn off the adjacent LED if the signal magnitude reachesa threshold level. Again, this design assumes that the light detected bythe photodiode is always due in substantial part to the light emitted bythe adjacent LED. Under these embodiments the LED-Photodiode pairs on asubstrate may operate as autonomous units.

The catheter may have a 1:1 ratio of LED chips to photodiode chips,e.g., as in the embodiments of arrays of LED-photodiode pairs. In otherembodiments the ratio may be 2:1 (meaning two LED to every photodiode),3:1, 4:1. The selected ratio and logic used to determine which LEDs toturn on/off may depend on the type of anatomy being treated. Forexample, irregular or unpredictable light scatter or reflectionproperties due to the geometry of the anatomy may require moresophisticated logic. When the walls of an anatomy are smooth, andcylindrical like (as in the illustrated example), then a more simplelogic may be the preferred choice.

FIGS. 3A-3B illustrate schematically aspects of embodiments justdescribed. FIG. 3A depict the light intensities of the emitted andreflected light for LED-photodiode array 31 c from FIG. 1. For ease ofillustration, the balloon 7 of the catheter 1 is not drawn in FIG. 3A.Here the LEDs for array 31 c are designed by clear boxes and referred toas L1, L2, L3, L4 . . . L10. The photodiodes are designated by hashboxes and referred to as P1, P2, P3, . . . P10. Opposing the array 31 cis a section of tissue. The intensity of emitted light from each of theLEDs is E1 and the intensity of the reflected light is R1, R2 or R3.

A section of tissue opposing LEDs L4, L5, L6 and L7 contains abnormaltissue, whereas the section of tissue opposing LEDs L1-L3 and L8-L10 ishealthy. Because a tumorous tissue can have different light reflectingproperties from healthy tissue, the reflected light for P4-P7 issignificantly different in magnitude from P1-P3 and P8-P10. Inparticular, the healthy tissue will tend to reflect more light than theabnormal tissue. As such, there is a higher return energy flux detectedby photodiodes that receive light reflected from healthy tissue. This isdepicted in FIG. 3A by the different intensities of reflected light R1,R2 and R3 in FIG. 3A. The light emitted from the LEDs is depicted by E1.

Distinguishing light characteristic of tissue may be used as thecriteria to selectively turn on or off LEDs. Thus, a local presence of atissue type, or transition between tissue types may be inferred based onthe signals produced by photodiodes in response to the variation inreflect light intensity. FIG. 3B depicts the distribution of LEDs turned“on” verses those turned “off” as a result of the reflected lightdistribution depicted in FIG. 3A. Since photodiodes P4-P7 received anamount of reflected light resulting in an electrical signal having amagnitude less than some predetermined amount (call it “X”), the LEDsassociated with these photodiodes were turned on to photo-activate aphoto-sensitive substance in the tissue, i.e., the abnormal tissueopposing LEDS P4-P7. The LEDs associated with P1-P3 and P8-P10 areturned off since the magnitude of the light energy detected by thesephotodiodes resulted in an electrical signal above the threshold X(indicating the presence of healthy tissue).

In other embodiments, a detected magnitude of light energy above athreshold may instead cause an LED to turn on, rather than off. Forexample, when light energy is desirable for purposes of degrading adrug's potency in healthy tissue that is adjacent to cancerous tissue,but without affecting the drug's potency in the cancerous tissue, LEDswould be turned on if the magnitude of the electrical signal at thecorresponding photodiode is greater than X.

As depicted in FIG. 3A, the LED-photodiode pair (L7, P7) is located at atransition zone between healthy and abnormal tissue. In this area, thereflected light R3 may produce an electrical signal much greater thanthe signal corresponding to R1 yet still less be less than the thresholdX. In the examples described above, L7 would be turned on since themagnitude of the signal is less than X. In other embodiments a criterionfor turning on/off an LED may instead be based on whether the signalfalls within a range of values, as opposed to whether it is above orbelow a single value. In still other embodiments, a mean of severalreceived electrical signals may be compared to a value. These signalsmay be obtained from changes in the light distribution resulting fromslight perturbations in the catheter's placement. Related criteria forturning an LED on/off would be to protect healthy tissue as the priorityover ensuring that the substance in the abnormal tissue is everywherephoto-activated, in which case L7 may instead be turned off since itappears to cover healthy as well as abnormal tissue (or, in the case ofwhen healthy tissue is being protected by supplying a drug-degradinglight energy, L7 would be turned on). Other criteria for turning LEDs onor off would be the optimization of the available power. When less LEDsare used, the available energy flux per LED goes up for a constantsource of available power supplied to the distal portion 12. It may bemore effective to deliver a higher energy flux per LED by turning offLEDs that may be positioned opposite both healthy and abnormal tissue(rather than turning on LEDs that illuminate both abnormal and healthytissue) so as to ensure photo-activation (or photo-degradation, as thecase may be) of at least some of the photo-sensitive substance.

A method for activating photosensitizers absorbed in abnormal tissue,but not adjacent, healthy tissue is depicted in the flow diagram of FIG.4. A photosensitizer is deposited, injected, etc. into the body suchthat tissue at the treatment area absorbs this photo-sensitivesubstance. Next, the catheter 1 is delivered to the treatment area,e.g., percutaneously. The balloon 7 is then inflated and pressed againstthe tissue. This provides a light path from/to the light detectors andemitters. As such, the balloon 7 may be thought of as ablood-displacement feature for displacing blood from the treatment areaso that there is a clear line of sight between a LED/photodiode andopposing tissue. Preferably, neither the inflation fluid nor the balloonmembrane diffuse, refract or reflect any appreciable amount of light.

The operator may then initiate the on-board control, e.g., supply powerto controller 34. When on-board control begins, a determination is madeas to which LEDs are positioned opposite healthy tissue and/or whichLEDs are positioned opposite abnormal tissue, e.g., lipid-rich tissuesuch as atheroma which tends to absorb and scatter more light thanhealthy tissue. LEDs may thereafter be controlled by a closed-loopelectronic control system residing at the catheter distal portion 12.The program may be initiated by communicating a “start” signal from theproximal portion 14 to the controller 34 or simply energizing a circuitlocated at the distal portion 12. Once initiated, LEDs may be controlledautonomously by the controller 34. According to these embodiments theoperator need not monitor or decide which individual LEDs are turnedon/off during the therapy. For example, any of the examples of logic andcircuit architecture disclosed earlier, including the controller 34,circuit board 30 (or both) may be programmed to decide which LEDS shouldbe turned on to photo-activate the substance in tissue and/or which LEDshould be turned off based on, e.g., an electrical signal correspondingto a threshold reflected light intensity “X”, on-off cycling of LEDs,etc. (as discussed earlier). Further examples follow.

As depicted in FIG. 4, after initiating the controller 34 a timer “t” isinitially set to a constant T. The controller 34 then performs acalibration routine 34 a because “t=T”. This calibration routine mayfirst turn “on” all LEDs then decide which LEDs to turn “off”. Forexample, the controller 34 activates all LEDs and then turns off any LEDwhere the signal produced at the corresponding photodiode (e.g.,photodiode P1 of the LED-photodiode pair (L1, P1) depicted in FIG. 3A)exceeds a maximum value X (as depicted in block 34 b of FIG. 4). Forembodiments of a medical device intended to supply light energy forpurposes of drug degradation (as opposed to drug-activation), block 34 bwould instead turn on an LED if the electrical signal exceeded the valueX.

After this initialization routine, the LEDs that were set to “ON” areused to photo-activate substance in the tissue while the remaining LEDsare left off. After a period of time has elapsed equal to, or exceedingT (as depicted schematically by the counter “t=t+1” and decision point“t=T?”) the calibration routine 34 a is repeated. Preferably, thecalibration routine is repeated on a regular basis to automaticallyaccount for any intentional or unintentional movement of the catheter inthe body. Further, it is contemplated that the calibration routine maybe sufficiently brief to avoid significant unintentional activation ordegradation of photosensitizer should there be intentional orunintentional movement of the catheter in the body. As such, the lightdistribution may automatically update without requiring direct operatorinvolvement.

The bandwidth of light used to photo-activate may be NIR, IR, visible orUV. The catheter 1 may also include a circuit for communicating acontrol signal to the operator that indicates the number of LEDs thatthe controller has decided should be used to treat tissue (transmittedover cable 38). From this information the operator may control/monitorthe energy flux per unit area being supplied to tissue. In otherembodiments the controller 34 may be programmed to control the powersupplied to the LEDs to ensure that the energy flux does not exceed amaximum, or to optimize the LEDs turned on/off as a function of therange of energy flux needed to treat tissue, e.g., between 15-50 J/cm².

According to others aspect of the disclosure, a catheter includes alight source, or is coupled to an extracorporeal light source. The lightemitted from the catheter at its distal portion may be filtered by afilter provided by the balloon membrane according to some embodiments.In other embodiments a catheter has a light emitting member at alocation distal and/or proximal of a balloon. A catheter according tothese embodiments may be used to achieve a desired activation ordegradation of a photo-sensitive substance using light energy. Methodsaccording to these embodiments include the delivery of a drug coatedballoon or DES to a target tissue.

Referring to FIG. 5, a balloon catheter 100 is depicted within a vesselwith its balloon in the expanded state. The catheter 100 is guided tothis treatment area along the guide wire 11 (as before). Unless notedbelow explicitly or implied by the context of the discussion, as will beappreciated, the catheter 100 possesses the same features as embodimentsof catheter 1 discussed earlier.

Catheter 100 includes a light source that is capable of emitting light120 from body 2 b, which as before may extend between ends 6 b, 6 a andwithin the balloon chamber 7 a (see FIG. 1). Light may emit over theentire length of the body 2 b, or only at select portions, such asnearest ends 6 a, 6 b. The light source may correspond to an LED array(as described earlier) or fiber optics. In the later case, a fiber opticbundle may be configured to transmit light originating at the proximalportion 14 of the catheter to a location near end 6 b, e.g., by passingthe fiber optic bundle through the inflation lumen. From this point, thebody 2 b may be configured to transmit light from its outer surface.Light collectors and/or diffusers may be incorporated into body 2 b toimprove/enhance the light distribution as it exits the fiber optics. Forexample, a focusing lens can first collect light exiting from the fiberoptics, followed by a diffusion lens, which forms the outer surface of 2b. A diffusion lens can provide uniform illumination of the surroundingtissue. An LED array may instead be chosen over fiber optics so that,e.g., light transmission losses from the proximal portion 14 to thedistal portion 12 are reduced. This LED array may be constructed on thesame type of circuit as discussed earlier in connection with FIGS. 1-3.Additionally, for embodiments of catheter 100 the array(s) may containonly LEDs, i.e., the circuit board(s) need not also include photodiodechips; although in some embodiments photodiodes may be used as this canprovide additional advantages in view of the disclosure. Examples ofsuitable light sources for light-emitting catheters are described inU.S. Pat. No. 7,344,528, U.S. Pat. No. 5,800,478, U.S. Pat. No.7,252,677 and U.S. Pat. No. 6,749,623.

According to embodiments of the catheter 100, the membrane 61 of balloon60 may have a combination of balloon membrane material (i.e., theportions 62 and 66 b, 66 a) that substantially prevent all wavelengthsof light from passing through the membrane walls, and membrane material,or windows 64 b, 64 a that permit a wide or narrow bandwidth of light topass. As such, tissue may be exposed to light energy at locations wherewindows, e.g., 64 b and 64 a, are present while portion 62 preventslight energy within the balloon from reaching tissue. Portions 66 may beopaque.

According to the following example (depicted in FIG. 5), the catheter100 is used to supply drug-degrading light energy to healthy tissue. Assuch, the light-blocking portion of the balloon membrane (portion 62) isplaced opposite the target tissue and the windows 64 opposite thehealthy tissue. In other embodiments, the catheter 100 may be configuredto provide drug-activating light energy to a target tissue. For theseembodiments, portion 62 may be made from transparent balloon materialand portions 64 from light-blocking balloon material.

In the case of supplying drug-degrading light energy according to someembodiments, a drug, e.g., Everolimus, is combined with aphotosensitizer and deposited on portion 62. The objective is to deposita full dosage of active drug to the target tissue but not thesurrounding tissue (designated “adjacent tissue” in FIG. 5). This isachieved by exposing the adjacent tissue to light that degrades thedrug's potency (due to the activation of a photosensitizer) should anydrug diffuse or otherwise come in contact with the adjacent, healthytissue. By this approach an undesirable presence of the drug at theadjacent tissue can be dealt with by degrading the drug's effectivenessusing light, e.g., UV light.

According to one method the catheter 100 is positioned so that portion62 is located at the target tissue. The balloon is expanded to place thedrug (deposited on the surface 62) in contact with the target tissue.The light source is then activated and light 120 emits from body 2 b.The tissue on each side of the target tissue is exposed to light sincein this case windows 64 are located near ends 6 b, 6 a. The targettissue is opposite the light-blocking membrane portion 62. Therefore,the target tissue does not receive the drug degrading light whereas theadjacent tissue does receive this light. After an energy flux has beenachieved sufficient to activate photosensitive material in the adjacenttissue, the drug's potency in the adjacent tissue is reduced.

FIG. 8 is a bar-chart showing the effectiveness of drug degradationusing light. The tests were conducted on Everolimus combined with aphotosensitizer in a solution of methanol. After a sufficient number oftrials were conducted, a mean and standard deviation of the percentrecovery for Everolimus was computed for each of two cases (as shown).The first case corresponds to the percent recovery of Everolimus withoutexposing the solution to UV light energy (referred to as“EV+Sensitizer+Dark”) and the second case corresponds to the percentrecovery of Everolimus when the solution is exposed to UV light energy(referred to as “EV+Sensitizer+Light”). As can be seen, there is morethan a 3% reduction in the potency of Everolimus after the solution wasexposed to UV light.

In some embodiments it may be important or at least desirable to achievea 100% degradation, so that one has absolute control over what tissue isexposed to the drug and which is not. However, depending on the rate ofdrug degradation, the toxicity of the degradation products, lightpenetration into the tissue, etc., it may be difficult or evenundesirable to achieve 100%. In other embodiments, one may attempt toreduce the amount of drug to a level out of its beneficial therapeuticrange, or specifically to a level below that which produces theundesirable effects we would like to prevent with this technique. Thepercent degradation would depend on the original drug dosing (amount ofdrug in the tissue) and the therapeutic window of the drug.

In one example, a sample available drug was used, which can beEverolimus. The drug was mixed with a photosensitizer in methanol, andexposed to a low intensity laser light source at the wavelength used toactivate the photosensitizer. The dark and light samples were then sentfor analysis of total drug concentration via HPLC (total content assay),which gives how much drug is contained in a specific volume of solution.The percent recovery is measured as the concentration of drug recovereddivided by the original concentration of the solution. A low (3%)difference, as depicted in the illustrative example, may be due to amultitude of factors. For example, the amount of drug used in theexperiment may be so great as to not reflect a noticeable differencebetween the exposed and unexposed. A concentration of 1.5 mg/ml ofEverolimus was used in 18 ml of methanol, which means a total drugcontent of 27 mg . . . a typical 28 mm stent contains about 130 ug ofEverolimus, which would be much more sensitive for a small change indrug content. The laser light source used was of a much lower power (25mW) than one that would be used in clinical practice (500 mW), but whichwas compensated for by applying a longer exposure time to equal thecomparable light dose that would be used in the clinic. The longexperiment time may lead to a greater amount of natural degradation inthe control (dark) sample, and when considering that the laser is of alow power to cause any additional degradation, a difference between thetwo in the illustrated example may not be as significant.

An ideal drug for use would contain a linkage which would make it moresensitive to either to degradation via light exposure or a degradationreaction with a reactive oxygen species triggered by light exposure tothe photosensitizer.

A catheter adapted for being used in a manner consistent with thedisclosure may also be configured with light-emitting members locatedproximal, distal or proximal and distal of a balloon assembly. Forexample, a catheter 200 depicted in FIG. 6 includes light emittingmembers 220 a and 220 b located proximal and distal of balloon assembly60. Light emitting members 220 a, 220 b may be used to degrade drug thatis diffused into, or otherwise comes in contact with the adjacenttissue. The target tissue is treated with the drug at full potency whenthe balloon places surface 62 (containing the drug-sensitizercombination) against the target tissue. When the light emitting members(e.g., respective distal and proximal portion(s) 220 a, 220 b ofcatheter shaft, which may include diffusion lenses coupled to fiberoptics or one or more LED array(s)) are activated, the light, e.g., UVlight, degrades the potency of the drug that is present in the adjacenttissue. One benefit of a catheter constructed in accordance with theembodiments relating to FIG. 6 is that a greater amount of adjacenttissue may be treated with light.

In other embodiments, a balloon catheter according to the disclosure maybe used in connection with the delivery of Drug Eluting Stents (DES).For example, a catheter may be configured to prevent or mitigate themixing of drugs carried by two DES, or reduce instances of double-dosingof the same drug when a DES is placed adjacent to another, previouslyimplanted DES, or when portions of these stents overlap each other.Referring to the example depicted in FIG. 7, a catheter 300 delivers DESB to a treatment area. DES B carries a DRUG B on its outer surface andwill be implanted adjacent a previously implanted DES A. This stentcarried a DRUG A which has begun to perfuse into the tissue (as shown).

A balloon assembly 60 portion of catheter 300, which carries DES B tothe treatment site, may include a light-blocking portion 66 of theballoon membrane 61 and a filter, light admitting or window 64 locatedat the proximal end, distal end or both ends of the balloon (alsocorresponding to ends of DES B). The length of the window(s) 64 maycorrespond to the amount of overlap intended between the two stents, orthe expected amount (or rate) of diffusion of DRUG A and/or DRUG B afterthe second stent has been implanted. DES B may span over the window orlight emitting portion of the balloon, or the catheter may have a secondlight emitting portion adjacent one or both ends of DES B forilluminating areas adjacent DES A. In some embodiments DES A may beprovided from the same stent provider as DRUG B, or a differentprovider. DRUG A may be the same as DRUG B or different. In someembodiments a stent delivery catheter may include windows at both endsto reduce the appearance of “end effects” as discussed earlier.

Referring again to the balloon catheter of FIG. 5, in some embodimentsthe portion 62 may permit a first wavelength of light to pass throughthe membrane walls to reach the target tissue, while portions 64 permita second wavelength to pass through the membrane walls to reachadjacent, healthy tissue. For example, a first portion of a balloonmembrane may permit only NIR light to pass through the walls whereas asecond portion allows all light to reach tissue. Referring again to FIG.6, in a variation of the catheter 200, one or more light sources producelight at light member(s) 220 and within the balloon chamber 7 a (seeFIG. 1). The light emitted from light member(s) 220 and from within theballoon chamber 7 a may be broad band light. The balloon membrane,however, permits only a narrow band of light from passing through itswalls, e.g., NIR. In these examples a drug-coated balloon catheter (orDES) may use light to both activate a photosensitive drug in targettissue and degrade that drug's potency in adjacent healthy tissue. Theseembodiments may be especially useful when treating tumors.

In accordance with the foregoing embodiments, a treatment agent caninclude, but is not limited to, an anti-proliferative, ananti-inflammatory or immune modulating agent, an anti-migratory, ananti-thrombotic or other pro-healing agent or a combination thereof.

The anti-proliferative agent can be a natural proteineous agent such ascytotoxin or a synthetic molecule or other substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; orCOSMEGEN available from Merck) (synonyms of actinomycin C1); all taxoidssuch as taxols, docetaxel, and paclitaxel, and paclitaxel derivatives;all olimus drugs including macrolide antibiotics such as tacrolimus,rapamycin (i.e., sirolimus) derivatives of which include40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,40-O-(3-hydroxy)propyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578 manufactured by AbbottLaboratories, Abbott Park, Ill.); everolimus (i.e., RAD-001); FKBP-12mediated mTOR inhibitors, perfenidone and prodrugs, co-drugs andcombinations thereof.

The anti-inflammatory agent can be a steroidal anti-inflammatory agent,a nonsteroidal anti-inflammatory agent, or a combination thereof. Insome embodiments, anti-inflammatory drugs include, but are not limitedto, alclofenac, alclometasone diproprionate, algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, deflazacort, desonide,desoximetasone, dexamethasone dipropionate, diclofenac potassium,diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazocort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, morniflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone sodium glycerate, perfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicyclicacid), salicyclic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof.

These agents can also have anti-proliferative and/or anti-inflammatoryproperties or can have other properties such as antineoplastic,antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic,antibiotic, antiallergic, antioxidant and/or cytostatic (i.e.cell-suppressing) properties. Examples of suitable treatment andprophylactic agents include synthetic inorganic and organic compounds,proteins and peptides, polysaccharides and other sugars, lipids, and DNAand RNA nucleic acid sequences having therapeutic, prophylactic ordiagnostic activities. Nucleic acid sequences include genes, antisensemolecules which bind to complementary DNA to inhibit transcription, andribozymes. Some other examples of other bioactive agents includeantibodies, receptor ligands, enzymes, adhesion peptides, blood clottingfactors, inhibitors or clot dissolving agents such as streptokinase andtissue plasminogen activator, antigens for immunization, hormones andgrowth factors, oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.,Adriamycin® from Pharmacia & Upjohn, Peapack, N.J.), and mitomycin(e.g., Mutamycin® from Bristol Myers Squibb Co, Stamford, Conn.).Examples of such antiplatelets, anticoagulants, antifebrin,antithrombins include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin,and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, thrombininhibitors such as Angiomax a (Biogen, Inc. Cambridge, Mass.), calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,dietary supplements such as various vitamins, and a combination thereof.Examples of cytostatic substances include angiopeptin, angiotensinconverting enzyme inhibitors such as captopril (e.g., Capoten® andCapozide® from Bristol Myers Squibb Co., Stamford, Conn.), cilazapril orlisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc.,Whitehouse Station, N.J.). An example of an antiallergic agent ispermirolast potassium. Other therapeutic substances or agents which maybe appropriate include α-interferon, and genetically engineeredepithelial cells. The foregoing substances are listed by way of exampleand are not meant to be limiting. Other treatment agents which arecurrently available or that may be developed in the future are equallyapplicable.

In accordance with the foregoing embodiments, the reactive oxygenproducing and light emitting photosensitizers include, but are nolimited to: Pyrrole-derived macrocyclic compounds, naturally occurringor synthetic porphyrins or derivatives thereof, naturally occurring orsynthetic chlorines and derivatives thereof, naturally occurring orsynthetic bacteriochlorins and derivatives thereof, syntheticisobacteriochlorins and derivatives thereof, phthalocyanines andderivatives thereof, naphthalocyamines and derivatives thereof,porphycenes and derivatives thereof, naphthalocyanines and derivativesthereof, porphycyanines and derivatives thereof, pentaphyrin andderivatives thereof, sapphyrins and derivatives thereof, texaphyrins andderivatives thereof, phenoxazine dyes and derivatives thereof,phenothiazines and derivatives thereof, chalcoorganapyrylium dyes andderivatives thereof, triarylmethanes and derivatives thereof, rhodaminesand derivatives thereof, fluorescenes and derivatives thereof,azaporphyrins and derivatives thereof, benzochlorins and derivativesthereof, purpurins and derivatives thereof, chlorophylls and derivativesthereof, squaraines and derivatives thereof, hypericin and derivativesthereof, verdins and derivatives thereof, xanthenes and derivativethereof, etc.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1-13. (canceled)
 14. A therapeutic method, comprising the steps of: providing a catheter having a balloon and light member located at a distal end of the catheter, the light member including a plurality of light-emitters and light detectors; locating the balloon and light member at a treatment area; locating abnormal tissue by detecting among the light detectors a variation in reflected light intensity; and initiating photodynamic therapy (PDT) including activating a portion of the light emitters based on the detected variation in reflected light intensity.
 15. The method of claim 21, further including the controller receiving a signal from a light detector, and the controller initiating PDT if the signal is equal to a first value and not emitting light if the signal is equal to a second value, or if the signal is between a third value and a fourth value.
 16. The method of claim 14, wherein the activating a portion of the light emitters includes activating light emitters that oppose abnormal tissue.
 17. The method of claim 16, wherein the activating a portion of the light emitters includes activating light emitters that do not oppose abnormal tissue.
 18. The method of claim 14, further including the step of inflating the balloon so as to press the balloon against tissue, wherein the balloon provides a line of site from the light member to the tissue.
 19. The method of claim 18, wherein the initiating PDT includes adjusting from the proximal portion of the catheter the light energy for PDT, and delivering the light energy for PDT through light emitters selected during the detecting step.
 20. The method of claim 19, wherein the light emitters include a light guide portion of the catheter coupled to an extracorporeal light source.
 21. The method of claim 14, the catheter including a controller disposed at the distal end, wherein the controller performs the initiating and detecting steps.
 22. The method of claim 14, wherein the detecting a variation in reflected light intensity further includes the steps of, for each of a plurality of light emitters and light detectors, receiving a signal generated from a light detector in response to reflected light from a light emitter, and if the signal is less than a predetermined value or within a predetermined range, using the light emitter for PDT.
 23. The method of claim 14, wherein the light emitters are light emitting diodes (LEDs) and the light detectors are photodiodes.
 24. The method of claim 14, wherein after PDT is initiated, further including repeating the detecting a variation in reflected light intensity after a predetermined amount of time has elapsed, followed by initiating the PDT a second time.
 25. The method of claim 14, further including a calibrating step performed prior to the detecting step, the calibrating step including, for each of the light emitters, activating the light emitter, and detecting an intensity of reflected light received for each of a plurality of nearby light detectors, wherein a nearby light detector has a highest intensity of reflected light for the activated light emitter, and the detecting step further including activating a first light emitter and determining whether the first light emitter opposes the abnormal tissue based on the magnitude of signal received at the nearby light detector for the first light emitter.
 26. A therapeutic method, comprising the steps of: providing a catheter having a balloon and light member located at a distal end of the catheter, and a first drug eluting stent (DES) mounted on the balloon, the first DES having a first overlapping portion and the drug includes a photo-sensitive drug; locating the first DES at the treatment area, wherein the treatment area includes a second DES having a second overlapping portion; placing the first DES at the treatment area such that the first overlapping area overlaps the second overlapping area; and activating the light member such that the light member emits light only upon the first overlapping area to thereby affect only the photo-sensitive drug at the overlapping area.
 27. A catheter having distal and proximal portions, comprising: a balloon, or a balloon and stent, and a light member located at the distal portion, the balloon or stent, respectively, configured for being placed in contact with tissue; and the light emitting member including a plurality of light-emitters and light detectors, wherein the light-emitters and detectors are arranged in pairs of light-emitters and light detectors such that a light detector is capable of detecting the light that is reflected from tissue receiving light emitted from an adjacent light-emitters; and a controller disposed at the distal portion and configured to perform the following steps: detect a variation in reflected light intensity among a plurality of light detectors, wherein the variation in reflected light intensity indicates locations where abnormal tissue opposes light-emitters; and initiate a photodynamic therapy (PDT) including activating a portion of the light emitters based on the detected variation in reflected light intensity.
 28. The catheter of claim 27, wherein the light emitters are light emitting diodes (LEDs) and the light detectors are photodiodes.
 29. The catheter of claim 28, wherein light emitting member includes a plurality of semiconductor substrates arranged in an array of LED and photodiode pairs.
 30. The catheter of claim 27, wherein the controller includes a circuit formed on a polyimide substrate and located at the distal portion. 